The long-term objective of the project is to explore the functional significance of the coexistence of acetylcholine and vasoactive intestinal polypeptide (VIP) in neurons of the cerebral cortex and the periphery. We wish to understand the implications of the coexistence of more than one signal substance in one neuron on the function and dysfunction of these neuronal systems, with the intention of discovering new sites or modes for drug action. For example, one may be able to utilize VIP, the coexisting peptide, to enhance the central cholinergic function, which would be of therapeutic value in Alzheimer's type senile dementia and Huntington's chorea. The general validity of the principles concerning coexistence and the behavior of neurons with coexisting transmitters during chronic drug treatment will also be studied on the serotonin/ substance P and noradrenaline/Neuropeptide Y systems, both of which are targets of the actions of antidepressant drugs. The effects of these drugs on the monoamines are well-documented, while the effects on the coexisting peptides are largely unknown, although they may play an important role in the therapeutic and side effects of these drugs. The study will concern the cross-feedback regulation of ACh and VIP release by ACh and VIP in fresh neurosurgical samples, as well as in rats which have been chronically treated with atropine or antidepressants with high anticholinergic affinity (e.g. amitryptiline). Changes in ACh/ VIP, 5-HT/ SP and NA/ NPY levels and turnover, and the subsequent changes in receptor number, affinity and coupling will be studied. We shall examine whether sub- or supersensitivity of the peptidergic system can evoke similar changes in the coexisting classical neurotransmitter system, and whether or not these changes could be reversed by administration of psychoactive drugs. We wish to define the degree of interrelatedness of coexisting neurotransmitters, and hope to find new classes of drugs which can change the activity of the monoaminergic system through an action on the coexisting neuropeptides. Our studies on rats will be followed up by investigations on fresh human neurosurgical material and on autopsy samples from brains afflicted by Alzheimer's type senile dementia and schizophrenia. We also plan to further develop a centrally active, non-tremorogenic oxotremorine analog (BM-5), which seems to act as a presynaptic antagonist and a postsynaptic agonist, and thereby represents a true enhancement of cholinergic transmission, with hope that it will be useful in treatment of confusion and Alzheimer disease.